bims-nurfca 2022-12-18 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2022‒12‒18
eleven papers selected by
Caner Geyik
Istinye University

KRAS G12D mutation eliminates reactive oxygen species through the Nrf2/CSE/H 2S axis and contributes to pancreatic cancer growth.
Knockdown of Nrf2 radiosensitizes glioma cells by inducing redox stress and apoptosis in hypoxia.
Alantolactone inhibits esophageal adenocarcinoma cells through nuclear factor erythroid 2-related factor 2-mediated ROS increment.
Autophagy inhibition and reactive oxygen species elimination by acetyl-CoA acetyltransferase 1 through fused in sarcoma protein to promote prostate cancer.
Nrf2 and Moirai: Life and Death Decisions on Cell Fates.
Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma.
Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling.
Dual role of Nrf2 in cancer: molecular mechanisms, cellular functions and therapeutic interventions.
Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies.
Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression.
Nrf2 affects hydroquinone-induces cell cycle arrest through the p16/pRb signaling pathway and antioxidant enzymes.

Acta Biochim Biophys Sin (Shanghai). 2022 Nov 25. 54(11): 1-9

KRAS G12D mutation eliminates reactive oxygen species through the Nrf2/CSE/H 2S axis and contributes to pancreatic cancer growth.

Kun Fan, Shulong Zhang, Xiaojian Ni, Sheng Shen, Jiwen Wang, Wentao Sun, Tao Suo, Han Liu, Xiaoling Ni, Houbao Liu.

  In pancreatic cancer, KRAS G12D can trigger pancreatic cancer initiation and development. Rapid tumor growth is often accompanied by excess intracellular reactive oxygen species (ROS) production, which is unfavorable to tumor. However, the regulation of intracellular ROS levels in KRAS mutant pancreatic cancer remains unclear. In this study, we establish BxPC3 stable cell strains expressing KRAS wild type (WT) and G12D mutation and find unchanged ROS levels despite higher glycolysis and proliferation viability in KRAS mutant cells than KRAS WT cells. The key hydrogen sulfide (H 2S)-generating enzyme cystathionine-γ-lyase (CSE) is upregulated in KRAS mutant BxPC3 cells, and its knockdown significantly increases intracellular ROS levels and decreases cell glycolysis and proliferation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by KRAS mutation to promote CSE transcription. An Nrf2 binding site (‒47/‒39 bp) in the CSE promoter is verified. CSE overexpression and the addition of NaHS after Nrf2 knockdown or inhibition by brusatol decreases ROS levels and rescues cell proliferation. Our study reveals the regulatory mechanism of intracellular ROS levels in KRAS mutant pancreatic cancer cells, which provides a potential target for pancreatic cancer therapy.

Keywords:  CSE; KRAS mutation; Nrf2; ROS; pancreatic cancer

DOI:  https://doi.org/10.3724/abbs.2022173
Transl Cancer Res. 2022 Nov;11(11): 4105-4116

Knockdown of Nrf2 radiosensitizes glioma cells by inducing redox stress and apoptosis in hypoxia.

Ting Tang, Yue Jia, Hui Liang, Yanling Han, Zixiang Cong, Handong Wang, Xiangjun Ji.

  Background: Radiotherapy remains a mainstream treatment for patients with glioma. Yet intrinsic radioresistance has largely compromised the efficacy of the treatment. Increasing concerns have been raised that overexpression of the Nrf2, along with a hypoxic tumor microenvironment, may have contributed to the deterioration of radiotherapy in tumors. So, this study investigated the role of Nrf2 in the radiation therapy of glioma cells in hypoxia.Methods: To determine the expression levels of Nrf2 and HIF-1α, surgical mastectomy specimens from patients with glioma in our institute were analyzed by immunohistochemical staining. Glioblastoma multiforme (GBM) cell lines U251 and U87 with Nrf2 knocked down were produced by transfection with lentiviral particles. Cell lines were treated with ionizing radiation in hypoxia in vitro, with expression and activity of Nrf2 examined by polymerase chain reaction and western blot. Reactive oxygen species (ROS) generation and cell apoptosis analysis were analyzed by flow cytometry.
Results: Nrf2 and its downstream pathway were upregulated in surgical specimens after radiotherapy, verified by GBM cell lines treated with in vitro ionizing radiation in hypoxia. Furthermore, knockdown of Nrf2 could induce the ROS generation and cell apoptosis levels after radiation.
Conclusions: Downregulation of Nrf2 could sensitize the lethal effect on GBM cells in vitro by enhancing oxidative stress and apoptosis in hypoxia.

Keywords:  Glioma; Nrf2; hypoxia; radiotherapy

DOI:  https://doi.org/10.21037/tcr-22-1420
Basic Clin Pharmacol Toxicol. 2022 Dec 11.

Alantolactone inhibits esophageal adenocarcinoma cells through nuclear factor erythroid 2-related factor 2-mediated ROS increment.

Jianhua Chen, Yunxiang Zhang, Rong Huang, Lihua Cao, Ying Zhang, Maowei Lian, Zuo Wang, Jiajia Jin, Chu Tang, Tingting Chen, Linli Yan, Linze Yu, Ruimin Tian, Xiaocong Xiang, Lijun Luo, Chunlei Yu.

  BACKGROUND: Esophageal adenocarcinoma (EAC) is a highly lethal cancer associated with a rapidly rising incidence and a poor prognosis. Alantolactone, a sesquiterpene lactone isolated from inula helenium, has anti-inflammatory, antimicrobial, neuroprotective activities, and anticancer properties.OBJECTIVE: In the present study, the anticancer effects of alantolactone on the human EAC cells were investigated in vitro and in vivo.
METHODS AND FINDINGS: After treated with alantolactone, the cell viability of KYAE-1, KYAE-2, OE19, OE33 cells reduced significantly compared with that of the control cells. Alantolactone induced apoptosis of the EAC cell lines by inhibiting the protein expression levels of nuclear factor erythroid2-related factor 2 (Nrf2). Furthermore, the apoptosis-inducing effect of alantolactone was enhanced by Nrf2 knockdown, while reduced by over-expression of Nrf2. Anti-oxidant α-tocopherol and glutathione can protect EAC cell lines against alantolactone A xenograft nude mice model showed that alantolactone can inhibit EAC growth in vivo.
CONCLUSIONS: Alantolactone inhibits esophageal adenocarcinoma cells through Nrf2-mediated Reactive oxygen species (ROS) increment. Alantolactone maybe a potential therapeutical candidate for treating EAC.

Keywords:  Alantolactone; Nrf2; ROS; adenocarcinoma; esophageal

DOI:  https://doi.org/10.1111/bcpt.13824
BMC Cancer. 2022 Dec 14. 22(1): 1313

Autophagy inhibition and reactive oxygen species elimination by acetyl-CoA acetyltransferase 1 through fused in sarcoma protein to promote prostate cancer.

Jingqian Guan, Xizi Jiang, Yaoxing Guo, Wenhui Zhao, Ji Li, Yizhuo Li, Ming Cheng, Lin Fu, Yue Zhao, Qingchang Li.

  BACKGROUND: Prostate cancer is a major health issue affecting the male population worldwide, and its etiology remains relatively unknown. As presented on the Gene Expression Profiling Interactive Analysis database, acetyl-CoA acetyltransferase 1 (ACAT1) acts as a prostate cancer-promoting factor. ACAT1 expression in prostate cancer tissues is considerably higher than that in normal tissues, leading to a poor prognosis in patients with prostate cancer. Here, we aimed to study the role of the ACAT1-fused in sarcoma (FUS) complex in prostate cancer and identify new targets for the diagnosis and treatment of the disease.METHODS: We conducted immunohistochemical analysis of 57 clinical samples and in vitro and in vivo experiments using a mouse model and plasmid constructs to determine the expression of ACAT1 in prostate cancer.
RESULTS: The relationship between the expression of ACAT1 and the Gleason score was significant. The expression of ACAT1 was higher in tissues with a Gleason score of > 7 than in tissues with a Gleason score of ≤7 (P = 0.0011). In addition, we revealed that ACAT1 can interact with the FUS protein.
CONCLUSIONS: In prostate cancer, ACAT1 promotes the expression of P62 and Nrf2 through FUS and affects reactive oxygen species scavenging. These effects are due to the inhibition of autophagy by ACAT1. That is, ACAT1 promotes prostate cancer by inhibiting autophagy and eliminating active oxygen species. The expression of ACAT1 is related to prostate cancer. Studying the underlying mechanism may provide a new perspective on the treatment of prostate cancer.

Keywords:  ACAT1; Autophagy; FUS; Prostate cancer; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12885-022-10426-5
Antioxid Redox Signal. 2022 Dec 12.

Nrf2 and Moirai: Life and Death Decisions on Cell Fates.

Yoko Yagishita, Dionysios V Chartoumpekis, Thomas W Kensler, Nobunao Wakabayashi.

SIGNIFICANCE: The transcription factor Nrf2 (NF-E2-related factor 2) plays an important role as a master regulator of the cellular defense system by activating transcriptional programs of Nrf2 target genes encoding multiple enzymes related to cellular redox balance and xenobiotic detoxication. Comprehensive transcriptional analyses continue to reveal an ever-broadening range of Nrf2 target genes, demonstrating the sophistication and diversification of Nrf2 biological signatures beyond its canonical cytoprotective roles.RECENT ADVANCES: Accumulating evidence indicates that Nrf2 has a strong association with the regulation of cell fates by influencing key processes of cellular transitions in the three major phases of the life cycle of the cell (i.e., cell birth, cell differentiation, and cell death). The molecular integration of Nrf2 signaling into this regulatory program occurs through a wide range of Nrf2 target genes encompassing canonical functions and those manipulating cell fate pathways.
CRITICAL ISSUES: A singular focus on Nrf2 signaling for dissecting its' actions limits in-depth understanding of its intersection with the molecular machinery of cell fate determinations. Compensatory responses of downstream pathways governed by Nrf2 executed by a variety of transcription factors and multifactorial signaling crosstalk require further exploration.
FUTURE DIRECTIONS: Further investigations using optimized in vivo models and active engagement of overarching approaches to probe the interplay of widespread pathways are needed to study the properties and capabilities of Nrf2 signaling as a part of a large network within the cell fate regulatory domain.

DOI: https://doi.org/10.1089/ars.2022.0200
Cancer Med. 2022 Dec 12.

Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma.

Guangda Yuan, Bowen Hu, Jun Ma, Chuanyu Zhang, Hongya Xie, Tengteng Wei, Yong Yang, Bin Ni.

  OBJECTIVE: Aberrant epigenetic remodeling represents a molecular hallmark in lung adenocarcinoma (LUAD). We aim to investigate the biological roles of SETDB2 and its underlying associations with oxidative stress, providing therapeutic targets for individualized treatment of LUAD.METHODS: Differential analysis was conducted via Limma package, and Kaplan-Meier analysis was performed with survival package. CCK-8, cell proliferation assay, transwell assay, and in vivo assays were conducted to assess the function of SETDB2. Western blot assay, RT-qPCR, and immunohistochemistry (IHC) were conducted to assess the expression levels of SETDB2/NRF2. Chromatin immunoprecipitation (ChIP) assay and ChIP-qPCR were conducted to assess the epigenetic roles of SETDB2.
RESULTS: We found that SETDB2 expression is decreased in tumor samples versus normal tissues in TCGA-LUAD cohort, LUAD-EAS cohort, GSE72094 dataset, and independent Soochow-LUAD dataset. Patients with low SETDB2 levels had a worse prognosis relative to those with high SETDB2. SETDB2 inhibition could significantly promote cell growth, migration ability, and stemness maintenance. Gene set enrichment analysis (GSEA) suggested that SETDB2 correlated with oxidative stress crosstalk and regulated NRF2 mRNA levels. ChIP assay suggested that SETDB2 mainly recruited the H3K9me3 enrichment at the NRF2 promoter region to suppress the mRNA levels of NRF2. Downregulated SETDB2 could activate NRF2 transcription and expression, thereby promoting its downstream targets, like NQO1, FTH1, and ME1. Functional experiments demonstrated that low SETDB2 allowed NRF2 to drive malignant processes of LUAD. SETDB2 overexpression attenuated the ability of NRF2 signaling to neutralize cellular reactive oxygen species (ROS) levels, leading to enhanced cell apoptosis. Overexpressed SETDB2 could inhibit tumor progression in vivo and further render LUAD cells sensitive to chemotherapy.
CONCLUSIONS: In conclusion, these findings uncovered the suppressive role of SETDB2 in LUAD. SETDB2 negatively regulates NRF2 signaling to modulate tumor progression, which creates a therapeutic vulnerability in LUAD.

Keywords:  LUAD; NRF2; SETDB2; chemotherapy; epigenetic regulation

DOI:  https://doi.org/10.1002/cam4.5451
Cancers (Basel). 2022 Nov 25. pii: 5812. [Epub ahead of print]14(23):

Elaiophylin Inhibits Tumorigenesis of Human Lung Adenocarcinoma by Inhibiting Mitophagy via Suppression of SIRT1/Nrf2 Signaling.

Jiali Ji, Ke Wang, Xinmin Meng, Hongqin Zhong, Xiyue Li, Hongqing Zhao, Guijuan Xie, Yunying Xie, Xun Wang, Xue Zhu.

  Lung adenocarcinoma (LADC), the most common type of lung cancer, is still one of the most aggressive and rapidly fatal tumor types, even though achievements in new therapeutic approaches have been developed. Elaiophylin as a C2 symmetrically glycosylated 16 macrolides has been reported to be a late-stage autophagy inhibitor with a potent anti-tumor effect on various cancers. This study investigated the anti-tumor effect of elaiophylin on human LADC for the first time in in vitro and in vivo models. The in vitro study in LADC A549 cells showed that elaiophylin significantly inhibited cell viability and induced cell apoptosis through the suppression of mitophagy and induction of cellular and mitochondrial oxidative stress. Proteomic analysis and molecular docking assay implicated that SIRT1 was likely the direct target of elaiophylin in A549 cells. Further mechanistic study verified that elaiophylin reduced Nrf2 deacetylation, expression, and transcriptional activity as well as cytoplasm translocation by downregulating SIRT1 expression and deacetylase activity. Additionally, SIRT1/Nrf2 activation could attenuate elaiophylin-induced mitophagy inhibition and oxidative stress. The in vivo study in the A549-xenograft mice model showed that the anti-tumor effect of elaiophylin was accompanied by the decreased expressions of SIRT1, Nrf2, Parkin, and PINK1. Thus, the present study reports that elaiophylin has potent anti-tumor properties in LADC, which effect is likely mediated through suppressing the SIRT1/Nrf2 signaling. In conclusion, elaiophylin may be a novel drug candidate for LADC and SIRT1 may be a new therapeutic target for such devastating malignancy.

Keywords:  SIRT1/Nrf2 signaling; elaiophylin; lung adenocarcinoma; mitophagy; oxidative stress

DOI:  https://doi.org/10.3390/cancers14235812
Mol Biol Rep. 2022 Dec 13.

Dual role of Nrf2 in cancer: molecular mechanisms, cellular functions and therapeutic interventions.

M Poornashree, Hitesh Kumar, Ramkishan Ajmeer, Rupshee Jain, Vikas Jain.

  BACKGROUND: Nrf2 regulates oxidative stress, which is essential for cellular function. Fundamental initiation of Nrf2 in many malignancies increases prosurvival genes & endorses tumour cell propagation via metabolic reprogramming, suppression of tumour programmed cell death, & increased cancer stem cell self-renewal potential. More specifically, Nrf2 has been associated with cancer cell chemoresistance, radioresistance & inflammation-induced carcinogenesis. METHODS AND RESULTS: Many Nrf2 inhibitors have been revealed for tumour treatment and targeting Nrf2 could be an effective cancer therapeutic method. Before spreading, cancer cells adapt to their surroundings. Cancer cells usually have mutations in tumor suppressor genes. In a variety of malignancies, somatic mutations & other anomalies in the Nrf2 genes, as well as renowned cancer suppressor genes including TP53, CDKN2A, PTEN & PIK3CA, have been found. In tumour cells, somatic mutations in the Nrf2 genes, as well as additional mechanisms that affect Nrf2 binding, and produce aberrant Nrf2 activation. Uncontrolled Nrf2 causes tumour cells to become resistant to antineoplastic drugs & reactive oxygen species (ROS), as well as guiding them toward metabolic reprogramming. CONCLUSIONS: As a result, Nrf2 has been studied as potential malignancy treatment target. We covered the pathways, mechanisms, and dual characteristics of Nrf2 in malignancy in this article. We also discussed how Nrf2 inhibitors are targeted against cancer in this review.

Keywords:  Anti-oncogenic; Anti-oxidation; Dual role; Nrf2; Pro-oncogenic; Therapeutics

DOI:  https://doi.org/10.1007/s11033-022-08126-1
Elife. 2022 Dec 16. pii: e80981. [Epub ahead of print]11

Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies.

CRUK IMAXT Grand Challenge Team

  Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilise clonal transcriptomics with WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, in mouse models of triple-negative breast cancer (TNBC) to understand response and resistance to therapy, including BET bromodomain inhibition and taxane-based chemotherapy. These analyses revealed oxidative stress protection by NRF2 as a major mechanism of taxane resistance and led to the discovery that our tumour models are collaterally sensitive to asparagine deprivation therapy using the clinical stage drug L-asparaginase after frontline treatment with docetaxel. In summary, clonal transcriptomics with WILD-seq identifies mechanisms of resistance to chemotherapy that are also operative in patients and pin points asparagine bioavailability as a druggable vulnerability of taxane-resistant lineages.

Keywords:  cancer biology; cancer therapy; chromosomes; gene expression; lineage tracing; mouse; single cell genomics; tumor heterogeneity

DOI:  https://doi.org/10.7554/eLife.80981
Cells. 2022 Dec 02. pii: 3893. [Epub ahead of print]11(23):

Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression.

Yao Guo, Taoyu Chen, Xueyi Liang, Shanmiao Gou, Jiongxin Xiong, Jing Cui, Tao Peng.

  Recently, evidence has shown that GOT1 expression is upregulated in pancreatic cancer tissues and promotes cancer development, but the specific mechanism remains unclear. We found that GOT1 expression was upregulated in pancreatic cancer cell-derived exosomes. When PANC-1 cells were incubated with exosomes alone or transfected together with si-GOT1, we found that exosomes enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-GOT1 reversed the effects of exosomes. The results of online bioinformatics database analysis indicated that CCR2 was a potential binding protein of GOT1 and is highly expressed in pancreatic cancer tissues. PANC-1 cells were transfected with pcDNA-CCR2 or si-CCR2, and it was found that pcDNA-CCR2 enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-CCR2 had an opposite effect. Next, exosome-treated cells were transfected with si-GOT1 alone or together with pcDNA-CCR2, and we found that exosomes promoted CCR2 expression, promoted cell proliferation and invasion, and inhibited ferroptosis, the transfection of si-GOT1 abolished the effect of exosomes, and the transfection of pcDNA-CCR2 again reversed the effect of si-GOT1. Furthermore, when exosome-treated cells were transfected with si-GOT1 alone or co-incubated with Nrf2 activator NK-252, we found that si-GOT1 reversed the promoting effect of exosomes on Nrf2 and HO-1 expression, as well as its inhibitory effect on ferroptosis, but this effect was abrogated by NK-252. In vivo studies showed that knockdown of GOT1 expression inhibited tumor formation compared with tumor tissues formed upon exosome induction, which was mediated by promoting ferroptosis via suppressing the protein expression of GOT1, CCR2, Nrf2 and HO-1 in tumor tissues.

Keywords:  CCR2; GOT1; exosome; ferroptosis; pancreatic cancer; the Nrf2/HO-1 axis

DOI:  https://doi.org/10.3390/cells11233893
Ecotoxicol Environ Saf. 2022 Dec 09. pii: S0147-6513(22)01229-5. [Epub ahead of print]249 114389

Nrf2 affects hydroquinone-induces cell cycle arrest through the p16/pRb signaling pathway and antioxidant enzymes.

Lin Chen, Lu Zhai, Yuting Gao, Zheming Cui, Lingxue Yu, Delong Zhu, Huanwen Tang, Hao Luo.

  Hydroquinone (HQ), a well-known carcinogenic agent, induces oxidative stress, cell cycle arrest, apoptosis, and malignant transformation. As an antioxidant actor, the nuclear factor erythroid 2-related factor 2 (Nrf2) drives adaptive cellular protection in response to oxidative stress. The human lymphoblastoid cell line (TK6 cells) is widely used as a model for leukemia researches. In the present study, we focused on exploring whether Nrf2 regulatory cell cycle in TK6 cells upon HQ treatment and the underlying mechanisms. The results showed that the cell cycle arrest in TK6 cells induced by hydroquinone was accompanied by activation of the Nrf2 signaling pathway. We further clarified that Nrf2 loss accelerated cell cycle progression from G0/G1 to S and G2/M phases and promoted ROS production by downregulating the expression of SOD and GSH. Western blotting analysis indicated that Nrf2 regulated cell cycle progression via p16/pRb signaling pathways. Therefore, we conclude that Nrf2 is engaged in HQ-induced cell cycle arrest as well through p16/pRb and antioxidant enzymes.

Keywords:  Cell cycle; Hydroquinone; Nrf2; p16

DOI:  https://doi.org/10.1016/j.ecoenv.2022.114389